NO315931B1 - Aqueous suspension of 9-hydroxy acid peridone fatty acid esters - Google Patents

Description

The present invention relates to a pharmaceutical composition in the form of a depot formulation for administration by intramuscular or subcutaneous injection, comprising: (1) as an active ingredient a therapeutically effective amount of a 9-hydroxyrisperidone fatty acid ester or a salt, or a stereoisomer or a stereoisomer mixture thereof and (2) a pharmaceutically acceptable carrier; wherein the pharmaceutically acceptable carrier is water and the active ingredient is suspended therein;

and a method for producing such a composition. The invention further relates to the use of such a pharmaceutical composition for the manufacture of a drug to treat schizophrenia, non-schizophrenic psychoses, behavioral disorders associated with neurodegenerative disorders, e.g. in dementia, behavioral disorders in mental retardation and autism, bipolar mania, depression, anxiety.

Risperidone is generic for 3-[2-[4-(6-fluoro-1,2-benzisoc-sazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl -4H-pyrido[1,2-a]pyrimidin-4-one. The preparation and pharmacological activity thereof are described in EP-0,196,132 (corresponding to US-4,804,663). Various conventional pharmaceutical dosage forms, including tablets, capsules, drops, suppositories, oral solutions and injectable solutions are exemplified therein. In practice, risperidone is normally administered as the base in a tablet or in a buffered, oral or intramuscular solution. Special solutions for oral or intramuscular administration are described in WO-96/01652.

Risperidone is a very potent drug that has a relatively narrow therapeutic index. It can cause unwanted side effects in overdose, most noticeably extra pyramidal syndrome (EPS) and to a lesser extent hypotension (due to peripheral alpha-adrenergic activity). In order to produce an antipsychotic effect in a patient, the total daily dose of risperidone ranges from approx. 2 to approx. 8 mg; for the relief of behavioral disturbances associated with neurodegenerative disorders, the total daily dose is usually less and typically in the range from approx. 0.5 to approx. 2 mg. Inter-individual differences and co-medication may necessitate dose titration in patients.

For a number of reasons, it is desirable to administer risperidone in a sustained or delayed release (depot) formulation which is effective over an extended period of time, preferably approx. 3 weeks or more.

WO-94/25460 (equivalent to EP-0,697,019) relates to the first such depot formulation and relates to the risperidone pamoate salt, a poorly water-soluble salt form of risperidone, which can be suspended in a pharmaceutically acceptable carrier, such as water or oil, and can be administered subcutaneously or intramuscularly . However, this salt has suboptimal pharmacokinetic properties. The release of the active ingredient from the formulations appears to be too rapid, resulting in relatively high initial plasma levels and an insufficient average duration of action, both characteristics should be improved in a truly effective depot formulation.

WO-95/13814 relates to sustained release formulations for parenteral administration in which risperidone is microencapsulated in a biocompatible, biodegradable wall-forming material (eg a polymer such as dl-(polylactide-co-glycolide)). The microencapsulated formulations have suitable pharmacokinetic properties, but require sophisticated manufacturing processes in an appropriately constructed facility. Accordingly, there is still a need for an effective and readily available depot formulation of risperidone or a risperidone-like compound.

Risperidone is known to be metabolised to 9-hydroxy-risperidone which has a pharmacological profile and potency comparable to that of the parent drug risperidone, but which has a longer elimination half-life. Risperidone is distributed to and eliminated from brain tissues more rapidly than its metabolite 9-hydroxyrisperidone. 9-Hydroxyrisperidone, its enantiomeric forms and C2-20 alkanoic acid esters thereof are described in EP-0,368,388 (corresponding to US-5,158,952 and US-5,254,556). The esters are considered to be potentially valuable prodrugs of the active metabolite of risperidone for use in the depot formulations.

In addition, the problems associated with the genetic polymorphology in the metabolism of risperidone to its active metabolite 9-hydroxyrisperidone may possibly be avoided by administering the metabolite or a long-acting prodrug thereof instead of risperidone itself.

In the metabolism of risperidone, indeed, debrisoquin-type genetic polymorphism plays a particular role. Accordingly, people can be phenotyped as poor, intermediate or extensive metabolizers on the basis of their metabolic ratio. The metabolic ratio is defined as the ratio of urinary recovery of debrisoquine to the 4-hydroxy metabolite of debrisoquine over a period of 8 hours after an oral intake of 10 mg of debrisoquine. In Oriental people, more than 99% of the population can be phenotyped as extensive metabolizers and poor metabolizers are rather rare. In the Caucasian race, however, only approx. 90% of the population is phenotyped as either extensive or intermediate metabolizers. About. 10% of the population are poor metabolizers and have insufficient amounts of the debrisoquine hydroxylase enzyme.

The duration of action and peak plasma levels of the active agents (risperidone and 9-hydroxyrisperidone) are dependent on the debrisoguine metabolic ration of the human being treated with risperidone. More specifically, high transient peak levels of risperidone are likely in poor metabolizers when the total daily amount is administered in a single dose. This can lead to unwanted side effects such as extra pyramidal syndrome (EPS) and hypotension.

Further inter-individual differences among humans, as regards the metabolism of risperidone, are due to the fact that in clinical practice the individuals to be treated with risperidone will usually receive additional drugs, e.g. tranguilizers such as phenothiazines, neuroleptics such as haloperidol, antidepressants etc, all of which can compete with risperidone for the debrisoquine hydroxylase enzyme. These drug interactions can seriously affect the metabolism of risperidone, especially in extensive metabolisers, and can result in the occurrence of side effects in patients receiving such additional medication.

The present invention is a result of the investigations into the development of an effective, well tolerated, sustained or delayed release (depot) formulation of a 9-hydroxyrisperidone alkanoic acid ester which is therapeutically effective for at least 3 weeks or more. By the expression "effective for at least 3 weeks or more", it is meant that the plasma levels of the active ingredient, 9-hydroxy-risperidone (free alcohol released by hydrolysis from the alkanoic acid ester), should be above approx. 10 ng/ml. On the other hand, the plasma levels should always remain below a threshold value of approx. 100 ng/ml to be able to call the formulation "effective". The threshold value is the average plasma level over a significant period of time, e.g. more than 15 min., above which patients may experience unwanted side effects, or conversely, the value of the plasma level below which the systemic tolerance of the formulation in question is still acceptable. The threshold value does not apply to transient, high plasma levels during a short period of time, e.g. less than 15 min., which is due to e.g. unexpected burst release of the active ingredient.

Both of the preceding features - plasma levels above a minimal therapeutic concentration but below an adverse effect-causing threshold value - are considered to be basic requirements that a current depot formulation should meet in order to be acceptable to the intended patients. Limiting the number of drug administrations and the incidence of unwanted side effects after each administration will undoubtedly improve patients' compliance with the therapy. Beyond these basic requirements, however, a number of additional needs can be identified which would further improve the patients' compliance; the two most significant are good local tolerance and easy administration.

Good local tolerance means minimal irritation and inflammation at the injection site; ease of administration refers to the needle size and length of time required to administer a dose of a particular drug formulation. In addition, depot formulations should be stable and have a shelf life of at least 2 years under normal conditions.

The investigations into the development of an effective, well-tolerated, sustained or delayed release (depot) formulation of a 9-hydroxyrisperidone-alkanoic acid ester which fulfills the above requirements led to the finding that a pharmaceutical composition in the form of a depot formulation for administration by intramuscular or subcutaneous injection should comprise: (1) as an active ingredient a therapeutically effective amount of a 9-hydroxyrisperidone fatty acid ester having the formula or a salt, or a stereoisomer or a stereoisomer mixture thereof, wherein R represents a straight C9-19 alkyl - radical; and (2) a pharmaceutically acceptable carrier; wherein the pharmaceutically acceptable carrier is water and the active ingredient is suspended therein.

Surprisingly, it appears that aqueous suspensions of 9-hydroxyrisperidone-C10-2oalkanoic acid esters (where R represents a straight C9-19 alkyl radical) are comparable and in some respects far better depot formulations than corresponding suspensions in non-aqueous, oil suspensions. This is quite unexpected because it is a kind of teaching in the art that depot formulations must include lipophilic drugs dissolved or suspended in a lipophilic medium. Until now, 9-hydroxyrisperidone C10-2oalkanoic acid esters have therefore been formulated in oils suitable for intramuscular administration, especially in sesame oil. Ci0-2oalkanoic acids are selected from the group consisting of decane- (capron), undecane-, dodecane- (laurin), tridecane-, tetradecane- (myristin), pentadecane-, hexadecane-(palmitin), heptadecane-, octadecane- (stearin), nonadecano and eicosanoic acid. Because of their limited aqueous solubility, it was generally assumed that the esters had to be suspended in oils. The ester having a C15 (pentadecyl) chain and the corresponding active ingredient, which is the 9-hydroxyrisperidone palmitate ester, was found to be the superior ester from a pharmacokinetic as well as from a tolerability point of view.

To further improve tolerance, several suspensions with different particle sizes of 9-hydroxy-risperidone palmitate tests in sesame oil, possibly in the presence of aluminum monostearate, were then considered. No significant difference between small or large prodrug particles could be established. The presence of aluminum monostearate only affected the viscosity of the formulation and its ease of administration.

In yet another set of experiments, it was found that by lowering the prodrug concentration in the depot formulation, tolerance of the administered formulation was further improved. Because oil suspensions prove difficult to take up in a syringe, experiments with less viscous carriers were initiated, especially with a medium chain triglyceride (Miglyol™) and, contrary to what the teaching says, with water as a carrier. The Miglyol™ formulations exerted significantly less systemic and local tolerance than the sesame oil-based formulations. However, to our great surprise, the aqueous suspensions of 9-hydroxy-risperidone-palmitates outperformed the sesame oil-based formulations. They have not only an appropriate duration of action, but also acceptable systemic and local tolerance, and a strikingly limited interindividual variation in pharmacokinetic properties.

The pharmacokinetic properties of the aqueous suspensions according to the present invention may further depend, to a limited extent, on the physicochemical properties of the solid 9-hydroxyrisperidone palmitate ester, such as particle size and crystal form.

Aqueous composition according to the present invention conveniently further comprises a suspending agent and a wetting agent, and optionally one or more preservatives, a buffer and an isotonizing agent. Special ingredients can act as two or more of these agents at the same time, e.g. behave as a preservative and a buffer, or behave as a buffer and an isotonizing agent.

Suitable suspending agents for use in the aqueous suspensions according to the present invention are cellulose derivatives, e.g. methyl cellulose, sodium carboxymethyl cellulose and hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, alginates, chitosan, dextrans, gelatin, polyethylene glycols, polyoxyethylene and polyoxypropylene ethers. Sodium carboxymethyl cellulose is preferably used in a concentration of 0.5 to 2%, more preferably 1% (weight/volume). Suitable wetting agents for use in the aqueous suspensions according to the present invention are polyoxyethylene derivatives of sorbitan esters, e.g. polysorbate 20 and polysorbate 80, lecithin, polyoxyethylene and polyoxypropylene esters, sodium deoxycholate. Polysorbate 20 is preferably used in a concentration of 0.05 to 0.3%, more preferably 0.05 to 0.2%, most preferably 0.1%

(weight/volume).

Preservatives are antimicrobial agents and antioxidants which can be selected from the group consisting of benzoic acid, benzyl alcohol, butylated hydroxyanisole, butylated hydroxytoluene, chlorobutol, a gallic acid, a hydroxybenzoate, EDTA, phenol, chlorocresol, metacresol, benzethonium chloride, myristyl-y-piccoline chloride, phenylmercury -silver acetate and thimerosal. In particular, benzyl alcohol can be used in a concentration of up to 2% (weight/volume), preferably up to 1.5% (weight/volume). Isotonizing agents are, e.g. sodium chloride, dextrose, mannitol, sorbitol, lactose, sodium sulfate. The suspensions conveniently comprise from 1 to 10% (w/v) isotonizing agent. Mannitol is preferably used in a concentration of from 2 to 7%, more preferably approx. 5%. Most preferably, however, it is used from approx. 1 to approx. 3% (weight/volume), especially from approx. 1.5 to approx. 2% (w/v) of one or more electrolytes to make the suspension isotonic, apparently because ions help prevent flocculation of the suspended ester. In addition, special electrolytes have the added benefit of buffering the aqueous suspension. Particularly preferred is the use of a mixture of disodium hydrogen phosphate (anhydrous) (typically approx. 0.9%

(w/v)) and sodium dihydrogen phosphate monohydrate (typically about 0.6% (w/v)) to make the solution isotonic, neutral and less prone to flocculation of the suspended ester therein.

A particularly desirable feature of an injectable depot formulation relates to the ease with which it can be administered. In particular, such an injection should be possible using a needle as fine as possible in as short a time as possible. This can be achieved with the aqueous suspensions of the present invention by keeping the viscosity below approx. 75 mPa.s, preferably below 60 mPa.s. Aqueous suspensions of this viscosity or lower can be both easily taken up in a syringe (e.g. from a bottle) and injected through a fine needle (e.g. a 21 G 1 H, 22 G 2 or Gl* needle) .

Ideally, aqueous suspensions according to the present invention will comprise as much prodrug as can be tolerated to keep the injection volume to a minimum, and as little of the other ingredients as possible. In particular, such a composition will comprise, based on the weight of the total volume of the composition: (a) from 3 to 20% (w/v) of the active ingredient; (b) from 0.05 to 0.2% (w/v) of a wetting agent; (c) from 0.5 to 2% (w/v) of a suspending agent; (d) up to 2% (w/v) of preservatives; (e) optionally one or more isotonizing agents sufficient to render the composition isotonic with cerium; and

(f) water q. pp. to 100%.

The aqueous suspensions according to the present invention can be prepared by following known procedures for preparing suspensions characterized by mixing the active ingredient closely with the carrier.

Such a method may include the steps:

(a) stirring the wetting agent with the water; (b) adding the preservative to the mixture while stirring; (c) dispersing the suspending agent in the mixture while stirring; (d) optionally dissolving the isotonizing agent in the mixture while stirring; (e) dispersing the active ingredient in the mixture while stirring, followed by homogenizing the mixture.

In addition, the present invention relates to the use of a composition as described previously for the preparation of a drug to treat schizophrenia, non-schizophrenic psychoses, behavioral disorders associated with neurodegenerative disorders, e.g. in dementia, behavioral disorders in mental retardation and autism, bipolar mania, depression, anxiety.

The compositions of the invention can be used to treat warm-blooded animals, especially humans suffering from schizophrenia, non-schizophrenic psychoses, behavioral disorders associated with neurodegenerative disorders, e.g. in dementia, behavioral disorders in mental retardation and autism, bipolar mania, depression, anxiety, by administration of a therapeutically effective amount of an aqueous suspension as previously described. Typically, the formulation will be administered approximately every 3 weeks or even longer intervals where possible. The dosage should range from approx. 2 to 4 mg/kg body weight.

The following examples are intended to illustrate the present invention.

Experimental part

A. Preparation of 9-Hydroxyrisperidone Palmitate Testers.

tf,tf'-dicyclohexylcarbodiimide (1.39 g; 6.8 mmol) was added to a solution of hexadecanoic acid (1.54 g; 6 mmol) in dichloromethane (140 mL) and stirred at room temperature for 10 min. 9-Hydroxyrisperidone (2.13 g; 5 mmol) was added to the reaction mixture, followed by 4-pyrrolidinopyridine (93 mg; 0.63 mmol). The mixture was stirred for three days at room temperature. Water (200 mL) was added to the reaction mixture and this was extracted three times with chloroform (100 mL). The combined organic phases were dried (MgSO 4 ), filtered and evaporated. The mixture was triturated in diisopropyl ether (100 mL), filtered and recrystallized in isopropanol (60 mL). The crystals were filtered off and dried, yielding 9-hydroxyrisperidone palmitate ester (2.67 g; 80.4%).

B. Composition examples.

Each of the formulations below was prepared according to the following general recipe: Humectants were stirred with the water at room temperature and preservatives were added thereto. While stirring, the suspending agent was dispersed in the mixture, and the isotonizing agent - if any - was added. Then the active ingredient was dispersed into the stirred mixture which was then homogenized and filtered on sterile containers. All ingredients and apparatus used during the preparation of the aqueous suspensions were sterile. In the tables below, all concentrations are expressed as % weight by volume of the total formulation [%(weight/volume)]. Formulation 1 ( Fl ) Physico-chemical properties of Fl Formulation 2a. 2b oa 2c ( F2a . F2b . F2c ) #The ester was ground and sieved into three fractions: F2a(particle size< 10 nm) viscosity = 19 mPa.s F2b(10 \ un< particle size<30 \ im) viscosity = 29 mPa. s F2c(particle size>30 (im) viscosity = 32 mPa.s pH = 6.86

osmolality = ± 280 mOsm/kg

Formulation 3a. 3b and 3c ( F3a . F3b . F3c )

#The ester was ground and sieved into three fractions: Formulation 4 ( F4 )

#The ester was milled and sieved using appropriate nominal standard test sieves, yielding active ingredient having a particle size distribution as follows:

90% of the particles (by volume)>0.5um

50% of particles (by volume)>5um

10% of the particles (by volume)>15 µm

The ester was sterilized by irradiation with 25 kGy <90>Y and mixed with the solvent (filtered through a 0.22 µm membrane filter and autoclaved for 30 min at 121°C) under sterile conditions.

pH=7

viscosity = ±10 mPa.s

osmolality= ±450 mOsm/kg

the injectability through a 22G IX needle created no problem.

Formulation 5a. 5b and 5c ( F5a. F5b. F5c)

C. Pharmacological examples

Cl. Pharmacological testing of Fl and analogous oil formulations

Fl was administered intramuscularly at 2.5 mg/kg body weight in 4 beagle dogs using a 21 G needle. In the same experiment, a corresponding formulation based on Miglyol™ (Fa) and one based on sesame oil (F|3) were used, as well as a suspension comprising 9-hydroxyrisperidone decanoate in sesame oil (Fy). Thus, the Miglyol™ formulation was administered using a 21 G needle, but both sesame oil-based formulations had to be administered using a 19 G needle. The following pharmacokinetic parameters were calculated from the experimental data:

Claims (10)

1. Pharmaceutical composition in the form of a depot formulation for administration by intramuscular or subcutaneous injection, comprising: (1) as an active ingredient a therapeutically effective amount of one 9-hydroxyrisperidone fatty acid ester having the formula or a salt, or a stereoisomer or a stereoisomer mixture thereof, where R represents a straight C9-19 alkyl radical; and (2) a pharmaceutically acceptable carrier; wherein the pharmaceutically acceptable carrier is water and the active ingredient is suspended therein. 2. Composition according to claim 1, where R represents a straight Cis (pentadecyl) chain and the active ingredient is 9-hydroxyrisperidone palmitate esters. 3. Composition according to claim 1, wherein the composition further comprises a suspending agent and a wetting agent, and optionally one or more of a preservative, a buffer and an isotonizing agent. 4. Composition according to claim 3, where the suspending agent is sodium carboxymethyl cellulose and the wetting agent is polysorbate 20. 5. Composition according to claim 4, where the preservative is benzyl alcohol and the isotonizing agent is mannitol or a phosphate buffer. 6. Composition according to claim 1, which has a viscosity lower than 75 mPa.s. 7. Composition according to claim 1, comprising based on weight of total volume of the composition: (a) from 3 to 20% (w/v) of the active ingredient; (b) from 0.05 to 0.2% (w/v) of a wetting agent; (c) from 0.5 to 2% (w/v) of a suspending agent; (d) up to 2% (w/v) preservatives; (e) optionally one or more isotonizing agents sufficient to render the composition isotonic with serum; and (f) water q. pp. to 100%. 8. Process for the preparation of a pharmaceutical composition according to any one of claims 1 to 7, characterized by closely mixing the active ingredient with the carrier. 9. Method according to claim 8, characterized in that it comprises the steps: (a) stirring the wetting agent with the water; (b) adding the preservative to the mixture while stirring; (c) dispersing the suspending agent in the mixture while stirring; (d) optionally dissolving the isotonizing agent in the mixture while stirring; (e) dispersing the active ingredient in the mixture while stirring, followed by homogenizing the mixture. 10. Use of a composition according to any one of claims 1 to 7 for the preparation of a medicament for treating schizophrenia, non-schizophrenic psychoses, behavioral disorders associated with neurodegenerative disorders, e.g. in dementia, behavioral disorders in mental retardation and autism, bipolar mania, depression, anxiety.